Cytokine mediated oligodendrocyte injury

脑室周围白质软化症(PVL)脑白质损伤的病理生理机制尚不清楚。包括氧自由基、谷氨酸和促炎细胞因子在内的多种因素可能参与了发育中的少突胶质细胞的损伤。本课题的重点是阐明细胞因子介导的损伤对发育中的少突胶质细胞的作用机制，明确它们在体内作为发育中白质损伤的介质的作用，并制定保护少突胶质细胞免受细胞因子介导的损伤的策略。我们的总体假设是全身或局部产生的细胞因子损伤发育中的少突胶质细胞，这种毒性可能是PVL的相关机制。为了解决这一假设，我们将追求以下具体目标：1.确定干扰素-γ、肿瘤坏死因子-α或内毒素对少突胶质细胞谱系中细胞存活的影响。假设：特定的促炎细胞因子或内毒素直接和特异性地介导对发育中的少突胶质细胞的损伤；2.确定内毒素激活的星形胶质细胞、小胶质细胞和巨噬细胞作为死亡介质对发育中的少突胶质细胞的作用。假设：脂多糖通过诱导中间细胞产生对发育中的少突胶质细胞有毒的因子，间接导致少突胶质细胞死亡；3.确定干扰素-γ介导的少突胶质细胞死亡的分子途径。假设：细胞因子介导的少突胶质细胞死亡的分子机制是通过诱导或激活含有信号分子的特定死亡结构域，或通过诱导介导的活性氧，或两者兼而有之。4.确定在体外向发育中的大脑白质立体定向注射内毒素或干扰素-γ是否会导致少突胶质细胞谱系的细胞死亡和低髓鞘形成。假设：通过局部注射特定的干扰素-γ或内毒素，可以在动物体内复制PVL病变的特征。

The pathophysiologic mechanism of white matter injury in periventricular leukomalacia (PVL) is not understood. Multiple factors, including oxygen free radicals, glutamate, and pro-inflammatory cytokines, likely contribute to injury of developing oligodendrocytes. The focus of this project is to elucidate the mechanism of action of cytokine mediated injury to developing oligodendrocytes, define their role in vivo as mediators of injury of developing white matter, and devise strategies to protect oligodendrocytes from cytokine mediated injury. Our overall hypothesis is that systemic or locally produced cytokines injure developing oligodendrocytes and that this toxicity is potentially relevant mechanism in PVL. To address this hypothesis we will pursue the following specific aims: 1. To determine the influence of IFN-gamma, TNF-alpha, or LPS (endotoxin) or survival of cells in the oligodendrocyte lineage. Hypothesis: Specific pro-inflammatory cytokines or LPS directly and specifically mediate injury to developing oligodendrocytes; 2. To determine the role of LPS-activated astrocytes, microglia and macrophages as mediators of death to developing oligodendrocytes. Hypothesis: LPS indirectly causes death of cells in the oligodendrocyte lineage by inducing an intermediate cell to produce factors toxic to developing oligodendrocytes; and 3. To determine the molecular pathway of IFN-gamma mediated oligodendroglial death. Hypothesis: The molecular mechanism of cytokine mediate mediated oligodendrocyte death occurs by induction or activation of specific death domain containing signaling molecules or by induction of reactive oxygen intermediated, or both. 4. To determine if endotoxin or IFN-gamma, that cause injury of cells in the oligodendrocyte lineage in vitro, will induce death of those cells and hypomyelination when injected stereotactically in vivo into developing cerebral white matter. Hypothesis: Characteristics of the PVL lesion can be reproduced in animals by focal introduction of specific IFN-gamma or endotoxin.